Sulfonamide derivatives

ABSTRACT

The present invention provides certain sulfonamide derivatives useful for potentiating glutamate receptor function in a mammal and therefore, useful for treating a wide variety of conditions, such as psychiatric and neurological disorders.

This is a 371 of PCT/US99/16964 filed Jul. 28, 1999 which claimspriority to U.S. Provisional Application No. 60/094,897 filed Jul. 31,1998.

The present invention relates to the potentiation of glutamate receptorfunction using certain sulfonamide derivatives. It also relates to novelsulfonamide derivatives, to processes for their preparation and topharmaceutical compositions containing them.

In the mammalian central nervous system (CNS), the transmission of nerveimpulses is controlled by the interaction between a neurotransmitter,that is released by a sending neuron, and a surface receptor on areceiving neuron, which causes excitation of this receiving neuron.L-Glutamate, which is the most abundant neurotransmitter in the CNS,mediates the major excitatory pathway in mammals, and is referred to asan excitatory amino acid (EAA). The receptors that respond to glutamateare called excitatory amino-acid receptors (EAA receptors). See Watkins& Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan,Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989);Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25(1990). The excitatory amino acids are of great physiologicalimportance, playing a role in a variety of physiological processes, suchas long-term potentiation (learning and memory), the development ofsynaptic plasticity, motor control, respiration, cardiovascularregulation, and sensory perception.

Excitatory amino acid receptors are classified into two general types.Receptors that are directly coupled to the opening of cation channels inthe cell membrane of the neurons are termed “ionotropic”. This type ofreceptor has been subdivided into at least three subtypes, which aredefined by the depolarizing actions of the selective agonistsN-methyl-D-aspartate (NMDA),alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), andkainic acid (KA). The second general type of receptor is the G-proteinor second messenger-linked “metabotropic” excitatory amino acidreceptor. This second type is coupled to multiple second messengersystems that lead to enhanced phosphoinositide hydrolysis, activation ofphospholipase D, increases or decreases in c-AMP formation, and changesin ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci.,14, 13 (1993). Both types of receptors appear not only to mediate normalsynaptic transmission along excitatory pathways, but also participate inthe modification of synaptic connections during development andthroughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol.Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15,41, (1990).

AMPA receptors are assembled from four protein sub-units known as GluR1to GluR4, while kainic acid receptors are assembled from the sub-unitsGluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer, MolecularPharmacology 44: 505-510, 1993. It is not yet known how these sub-unitsare combined in the natural state. However, the structures of certainhuman variants of each sub-unit have been elucidated, and cell linesexpressing individual sub-unit variants have been cloned andincorporated into test systems designed to identify compounds which bindto or interact with them, and hence which may modulate their function.Thus, European patent application, publication number EP-A2-0574257discloses the human sub-unit variants GluR1B, GluR2B, GluR3A and GluR3B.European patent application, publication number EP-A1-0583917 disclosesthe human sub-unit variant GluR4B.

One distinctive property of AMPA and kainic acid receptors is theirrapid deactivation and desensitization to glutamate. Yamada and Tang,The Journal of Neuroscience, September 1993, 13(9): 3904-3915 andKathryn M. Partin, J. Neuroscience, Nov. 1, 1996, 16(21): 6634-6647. Thephysiological implications of rapid desensitization, and deactivation ifany, are unknown.

It is known that the rapid desensitization and deactivation of AMPAand/or kainic acid receptors to glutamate may be inhibited using certaincompounds. This action of these compounds is often referred to in thealternative as “potentiation” of the receptors. One such compound, whichselectively potentiates AMPA receptor function, is cyclothiazide. Partinet al., Neuron. Vol. 11, 1069-1082, 1993. Compounds which potentiateAMPA receptors, like cyclothiazide, are often referred to as ampakines.

International Patent Application Publication Number WO 9625926 disclosesa group of phenylthioalkylsulphonamides, S-oxides and homologs which aresaid to potentiate membrane currents induced by kainic acid and AMPA.

Ampakines have been shown to improve memory in a variety of animaltests. Staubli et al., Proc. Natl. Acad. Sci., Vol. 91, pp 777-781,1994, Neurobiology, and Arai et al., The Journal of Pharmacology andExperimental Therapeutics, 278: 627-638, 1996.

It has, now been found that cyclothiazide and certain sulfonamidederivatives potentiate agonist-induced excitability of human GluR4Breceptor expressed in HEK 293 cells. Since cyclothiazide is known topotentiate glutamate receptor function in vivo, it is believed that thisfinding portends that the sulfonamide derivatives will also potentiateglutamate receptor function in vivo, and hence that the compounds willexhibit ampakine-like behavior.

The present invention provides compounds of formula I:

wherein

R¹ represents a naphthyl group or a phenyl, furyl, thienyl or pyridylgroup which is unsubstituted or substituted by one or two substituentsselected independently from halogen; nitro; cyano; hydroxyimino;(1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl;hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl;(CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO orOCONR¹³, R⁹ represents hydrogen, (1-10C)alkyl, (3-10 C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyland R¹⁰, R¹¹, R¹² and R¹³ each independently represents hydrogen or(1-10C)alkyl, or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together with the nitrogenatom to which they are attached form an azetidinyl, pyrrolidinyl,piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl;N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydro-thienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl;dihydrothiazolyl; (1-4C)alkoxycarbonyldihydrothiazolyl;(1-4C)alkoxycarbonyldimethyldihydrothiazolyl; tetrahydro-thienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; and a group of formulaR¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH orCH═CH, L^(a) and L^(b) each represent (1-4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen,nitro, cyano, hydroxyimino, (1-10C) alkyl, (2-10C)alkenyl,(2-10C)alkynyl, (3-8C)-cycloalkyl,4-(1,1-dioxotetrahydro-1,2-thiazinyl), halo(1-10C)alkyl,cyano(2-10C)alkenyl, phenyl, and (CH₂)_(z)X³R¹⁵ in which z is 0 or aninteger of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH), COO, OCO,CONR¹⁷, NR¹⁸CO, NHSO₂, NHSO₂NR¹⁷, NHCONH, OCONR¹⁹ or NR¹⁹COO, R¹⁵represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl,(1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl,(N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino-(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)-cycloalkyl, camphoryl or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, (1-4C)haloalkyl,di(1-4C)alkylamino and (1-4C)alkoxy and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group;

R^(2a) and R^(2b) each independently represent hydrogen, (1-6C)alkyl,(3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl,(1-4C)alkoxy(1-4C)alkyl, (1-6C)alkylN(1-4C)alkyl₂,(1-6C)alkylO(1-6C)alkyl, —CH₂furyl, (3-6C)cycloalkyl(1-6C)alkyl,(phenyl)₂(1-6C)alkyl, phenyl which is unsubstituted or substituted byhalogen, (1-4C)alkyl, (1-4C)alkoxy or (3-6C)cycloalkyl,phenyl(1-6C)alkyl which is unsubstituted or substituted by halogen,(1-4C)alkyl, (1-4C)alkoxy, or (3-6C)cycloalkyl, naphthyl which isunsubstituted or substituted by halogen, (1-4C)alkyl, (1-4C)alkoxy or(3-6C)cycloalkyl, naphthyl(1-6C)alkyl which is unsubstituted orsubstituted by halogen, (1-4C)alkyl, (1-4C)alkoxy or (3-6C)cycloalkyl,or

R^(2a) and R^(2b) together with the nitrogen atom to which they areattached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino,piperazinyl, hexahydroazepinyl or octahydroazocinyl group; and

either one of R⁵, R⁶, R⁷ and R⁸ represents hydrogen, (1-6C)alkyl;aryl(1-6C)alkyl; (2-6C)alkenyl; aryl(2-6C)alkenyl or aryl, or two of R⁵,R⁶, R⁷ and R⁸ together with the carbon atom or carbon atoms to whichthey are attached form a (3-8C) carbocyclic ring; and the remainder ofR⁵, R⁶, R⁷ and R⁸ represent hydrogen; or a pharmaceutically acceptablesalt thereof.

The present invention further provides a method of potentiatingglutamate receptor function in a mammal requiring such treatment, whichcomprises administering an effective amount of a compound of formula I.

According to another aspect, the present invention provides the use of acompound of formula I, or a pharmaceutically acceptable salt thereof asdefined hereinabove for the manufacture of a medicament for potentiatingglutamate receptor function.

In addition, the present invention provides the use of a compound offormula I or a pharmaceutically acceptable salt thereof for potentiatingglutamate receptor function.

The invention further provides a method of potentiating glutamatereceptor function in a mammal requiring such treatment, which comprisesadministering an effective amount of a compound of formula:

wherein

R¹ represents an unsubstituted or substituted aromatic or heteroaromaticgroup;

R^(2a) and R^(2b) each independently represent hydrogen, (1-6C)alkyl,(3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl,(1-4C)alkoxy(1-4C)alkyl, (1-6C)alkylN(1-4C)alkyl₂,(1-6C)alkylO(1-6C)alkyl, —CH₂furyl, (3-6C)cycloalkyl(1-6C)alkyl,(phenyl)₂(1-6C)alkyl, phenyl which is unsubstituted or substituted byhalogen, (1-4C)alkyl, (1-4C)alkoxy or (3-6C)cycloalkyl,phenyl(1-6C)alkyl which is unsubstituted or substituted by halogen,(1-4C)alkyl, (1-4C)alkoxy, or (3-6C)cycloalkyl, naphthyl which isunsubstituted or substituted by halogen, (1-4C)alkyl, (1-4C)alkoxy or(3-6C)cycloalkyl, naphthyl(1-6C)alkyl which is unsubstituted orsubstituted by halogen, (1-4C)alkyl, (1-4C)alkoxy or (3-6C)cycloalkyl, ,or

R^(2a) and R^(2b) together with the nitrogen atom to which they areattached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino,piperazinyl, hexahydroazepinyl or octahydroazocinyl group; and

either one of R⁵, R⁶, R⁷ and R⁸ represents hydrogen, (1-6C)alkyl;aryl(1-6C)alkyl; (2-6C)alkenyl; aryl(2-6C)alkenyl or aryl, or two of R⁵,R⁶, R⁷ and R⁸ together with the carbon atom or carbon atoms to whichthey are attached form a (3-8C) carbocyclic ring; and the remainder ofR⁵, R⁶, R⁷ and R⁸ represent hydrogen; or a pharmaceutically acceptablesalt thereof.

In this specification, the term “potentiating glutamate receptorfunction” refers to any increased responsiveness of glutamate receptors,for example AMPA receptors, to glutamate or an agonist, and includes butis not limited to inhibition of rapid desensitization or deactivation ofAMPA receptors to glutamate.

A wide variety of conditions may be treated or prevented by thecompounds of formula I and their pharmaceutically acceptable saltsthrough their action as potentiators of glutamate receptor function.Such conditions include those associated with glutamate hypofunction,such as psychiatric and neurological disorders, for example cognitivedisorders; neuro-degenerative disorders such as Alzheimer's disease;age-related dementias; age-induced memory impairment; movement disorderssuch as tardive dyskinesia, Hungtington's chorea, myoclonus andParkinson's disease; reversal of drug-induced states (such as cocaine,amphetamines, alcohol-induced states); depression; attention deficitdisorder; attention deficit hyperactivity disorder; psychosis; cognitivedeficits associated with psychosis; and drug-induced psychosis. Thecompounds of formula I may also be useful for improving memory (bothshort term and long term) and learning ability. The present inventionprovides the use of compounds of formula I for the treatment of each ofthese conditions.

The term “treating” (or “treat”) as used herein includes its generallyaccepted meaning which encompasses prohibiting, preventing, restraining,and slowing, stopping, or reversing progression, severity, or aresultant symptom.

The present invention includes the pharmaceutically acceptable salts ofthe compounds defined by formula I. A compound of this invention canpossess a sufficiently acidic, a sufficiently basic, or both functionalgroups, and accordingly react with any of a number of organic andinorganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt.

The term “pharmaceutically acceptable salt” as used herein, refers tosalts of the compounds of the above formula which are substantiallynon-toxic to living organisms. Typical pharmaceutically acceptable saltsinclude those salts prepared by reaction of the compounds of the presentinvention with a pharmaceutically acceptable mineral or organic acid oran organic or inorganic base. Such salts are known as acid addition andbase addition salts.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide,acetate, propionate, decanoate, caprylate, acrylate, formate,hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalatexylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, g-hydroxybutyrate, glycolate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,napththalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such asammonium or alkali or alkaline earth metal hydroxides, carbonates,bicarbonates, and the like. Such bases useful in preparing the salts ofthis invention thus include sodium hydroxide, potassium hydroxide,ammonium hydroxide, potassium carbonate, sodium carbonate, sodiumbicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. The potassium and sodium salt forms areparticularly preferred.

It should be recognized that the particular counterion forming a part ofany salt of this invention is usually not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole. It is further understood that the above salts may form hydratesor exist in a substantially anhydrous form.

As used herein, the term “stereoisomer” refers to a compound made up ofthe same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

The term “enantiomeric enrichment” as used herein refers to the increasein the amount of one enantiomer as compared to the other. A convenientmethod of expressing the enantiomeric enrichment achieved is the conceptof enantiomeric excess, or “ee”, which is found using the followingequation: ${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$

wherein E¹ is the amount of the first enantiomer and E² is the amount ofthe second enantiomer. Thus, if the initial ratio of the two enantiomersis 50:50, such as is present in a racemic mixture, and an enantiomericenrichment sufficient to produce a final ratio of 50:30 is achieved, theee with respect to the first enantiomer is 25%. However, if the finalratio is 90:10, the ee with respect to the first enantiomer is 80%. Anee of greater than 90% is preferred, an ee of greater than 95% is mostpreferred and an ee of greater than 99% is most especially preferred.Enantiomeric enrichment is readily determined by one of ordinary skillin the art using standard techniques and procedures, such as gas or highperformance liquid chromatography With a chiral column. Choice of theappropriate chiral column, eluent and conditions necessary to effectseparation of the enantiomeric pair is well within the knowledge of oneof ordinary skill in the art. In addition, the enantiomers of compoundsof formula I can be resolved by one of ordinary skill in the art usingstandard techniques well known in the art, such as those described by J.Jacques, et al., “Enantiomers, Racemates, and Resolutions”, John Wileyand Sons, Inc., 1981. Examples of resolutions include recrystallizationtechniques or chiral chromatography.

Some of the compounds of the present invention have one or more chiralcenters and may exist in a variety of stereoisomeric configurations. Asa consequence of these chiral centers, the compounds of the presentinvention occur as racemates, mixtures of enantiomers and as individualenantiomers, as well as diastereomers and mixtures of diastereomers. Allsuch racemates, enantiomers, and diastereomers are within the scope ofthe present invention.

The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

As used herein, the term “aromatic group” means the same as aryl, andincludes phenyl and a polycyclic aromatic carbocyclic ring such asnaphthyl.

The term “heteroaromatic group” includes an aromatic 5-6 membered ringcontaining from one to four heteroatoms selected from oxygen, sulfur andnitrogen, and a bicyclic group consisting of a 5-6 membered ringcontaining from one to four heteroatoms selected from oxygen, sulfur andnitrogen fused with a benzene ring or another 5-6 membered ringcontaining one to four atoms selected from oxygen, sulfur and nitrogen.Examples of heteroaromatic groups are thienyl, furyl, oxazolyl,isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl,isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, indolyl and quinolyl.

The term “substituted” as used in the term “substituted aromatic orheteroaromatic group” herein signifies that one or more (for example oneor two) substituents may be present, said substituents being selectedfrom atoms and groups which, when present in the compound of formula I,do not prevent the compound of formula I from functioning as apotentiator of glutamate receptor function.

Examples of substituents which may be present in a substituted aromaticor heteroaromatic group include halogen; nitro; cyano; hydroxyimino;(1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl;hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl;(CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO, OCONR¹³,R⁹ represents hydrogen, (1-10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl,pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R¹⁰,R¹¹, R¹² and R¹³ each independently represents hydrogen or (1-10C)alkyl,or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together with the nitrogen atom to whichthey are attached form an azetidinyl, pyrrolidinyl, piperidinyl ormorpholino group; N-(1-4C)alkylpiperazinyl;N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl;dihydrothiazolyl; (1-4C)alkoxycarbonyl dihydrothiazolyl;(1-4C)alkoxycarbonyl dimethyl-dihydrothiazolyl; tetrahydrothienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; and a group of formulaR¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH, orCH═CH, L^(a) and L^(b) each represent (1-4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen;nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl;(3-8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);halo(1-10C)alkyl, cyano(2-10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO,CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, NHSO₂NR¹⁷, OCONR¹⁹ or NR¹⁹COO,R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl,halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.

The term (1-10C)alkyl includes (1-8C)alkyl, (1-4C)alkyl and (1-4C)alkyl.Particular values are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.

The term (2-10C)alkenyl includes (3-10C)alkenyl, (1-8C)alkenyl,(1-6C)alkenyl and (1-4C)alkenyl. Particular values are vinyl andprop-2-enyl.

The term (2-10C)alkynyl includes (3-10C)alkynyl, (1-8C)alkynyl,(1-6C)alkynyl and (3-4C)alkynyl. A particular value is prop-2-ynyl.

The term (3-8C)cycloalkyl, as such or in the term (3-8C)cycloalkyloxy,includes monocyclic and polycyclic groups. Particular values arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andbicyclo[2.2.2]octane. The term includes (3-6C)cycloalkyl: cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term hydroxy(3-8C)cycloalkyl includes hydroxy-cyclopentyl, such as3-hydroxycyclopentyl.

The term oxo(3-8C)cycloalkyl includes oxocyclopentyl, such as3-oxocyclopentyl.

The term halogen includes fluorine, chlorine, bromine and iodine.

The term halo(1-10C)alkyl includes fluoro(1-10C)alkyl, such astrifluoromethyl and 2,2,2-trifluoroethyl, and chloro(1-10C)alkyl such aschloromethyl.

The term cyano(2-10C)alkenyl includes 2-cyanoethenyl.

The term (2-4C)alkylene includes ethylene, propylene and butylene. Apreferred value is ethylene.

The term thienyl includes thien-2-yl and thien-3-yl.

The term furyl includes fur-2-yl and fur-3-yl.

The term oxazolyl includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl.

The term isoxazolyl includes isoxazol-3-yl, isoxazol-4-yl andisoxazol-5-yl.

The term oxadiazolyl includes [1,2,4]oxadiazol-3-yl and[1,2,4]oxadiazol-5-yl.

The term pyrazolyl includes pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl.

The term thiazolyl includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl.

The term thiadiazolyl includes [1,2,4]thiadiazol-3-yl, and[1,2,4]thiadiazol-5-yl.

The term isothiazolyl includes isothiazol-3-yl, isothiazol-4-yl andisothiazol-5-yl.

The term imidazolyl includes imidazol-2-yl, imidazolyl-4-yl andimidazolyl-5-yl.

The term triazolyl includes [1,2,4]triazol-3-yl and [1,2,4]triazol-5-yl.

The term tetrazolyl includes tetrazol-5-yl.

The term pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.

The term pyridazinyl includes pyridazin-3-yl, pyridazin-4-yl,pyridazin-5-yl and pyridazin-6-yl.

The term pyrimidyl includes pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl and pyrimidin-6-yl.

The term benzofuryl includes benzofur-2-yl and benzofur-3-yl.

The term benzothienyl includes benzothien-2-yl and benzothien-3-yl.

The term benzimidazolyl includes benzimidazol-2-yl.

The term benzoxazolyl includes benzoxazol-2-yl.

The term benzothiazolyl includes benzothiazol-2-yl.

The term indolyl includes indol-2-yl and indol-3-yl.

The term quinolyl includes quinol-2-yl.

The term dihydrothiazolyl includes 4,5-dihydrothiazol-2-yl, and the term(1-4C)alkoxycarbonyldihydrothiazolyl includes4-methoxycarbonyl-4,5-dihydrothiazol-2-yl.

The term “—CH₂furyl” includes the following:

The term “(1-6C)alkyl O(1-6C)alkyl” includes the following:

The term “(3-6C)cycloalkyl(1-6C)alkyl” includes the following:

The term “(phenyl)₂(1-6C)alkyl” includes the following:

The term “phenyl(1-6C)alkyl” includes the following:

Examples of phenyl(1-6C)alkyl which is substituted by halogen,(1-4C)alkyl or (1-4C)alkoxy include the following:

Preferably either one or two of R⁵, R⁶, R⁷ and R⁸ represents(1-6C)alkyl, aryl(1-6C)alkyl, (2-6C)alkenyl, aryl(2-6C)alkenyl or aryl,or two of R⁵, R⁶, R⁷ and R⁸ together with the carbon atom or carbonatoms to which they are attached form a (3-8C)carbocyclic ring; and theremainder of R⁵, R⁶, R⁷ and R⁸ represent hydrogen.

Examples of a (1-6C)alkyl group represented by R⁵, R⁶, R⁷ and R⁸ aremethyl, ethyl and propyl. An example of an aryl(1-C)alkyl group isbenzyl. An example of a (2-6C)alkenyl group is prop-2-enyl. An exampleof a (3-8C)carbocyclic ring is a cyclopropyl ring.

More preferably R⁶ and R⁷ represent hydrogen.

Preferably R⁵ and R⁸ each independently represents hydrogen or(1-4C)alkyl, or together with the carbon atom to which they are attachedform a (3-8C) carbocyclic ring.

More preferably R⁸ represents methyl or ethyl, or R⁵ and R⁸ togetherwith the carbon atom to which they are attached form a cyclopropyl ring.When R⁸ represents methyl or ethyl, R⁵ preferably represents hydrogen ormethyl.

Especially preferred are compounds in which R⁸ represents methyl and R⁵,R⁶ and R⁷ represent hydrogen.

Preferably R³ and R⁴ each represent methyl.

Examples of values for R^(2a) and R^(2b) are hydrogen, methyl, ethyl,propyl, 2-propyl, butyl, t-butyl, 2-methylpropyl, cyclohexyl,trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl, ethenyl,prop-2-enyl, methoxyethyl, phenyl, 4-fluorophenyl,

Preferably R^(2a) and R^(2b) are hydrogen, ethyl, or 2-propyl.

Examples of values for R⁹ are hydrogen, methyl, ethyl, propyl,isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 2-pyrrolidinyl, morpholino or 2-tetrahydrofuryl.

Examples of values for R¹⁵ are hydrogen, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, benzyl, 2,2,2-trifluoroethyl,2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl,2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 1-(5-dimethylamino)naphthyl, and 2-thienyl.

X¹ preferably represents O, CO, CONH or NHCO.

z is preferably 0.

R⁹ is preferably (1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl,pyrrolidinyl, morpholino or tetrahydrofuryl.

Particular values for the groups (CH₂)_(y)X¹R⁹ and (CH₂)_(z)X³R¹⁵include (1-10C)alkoxy, including (1-6C)alkoxy and (1-4C)alkoxy, such asmethoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3-10C)alkenyloxy,including (3-6C)alkenyloxy, such as prop-2-enyloxy; (3-10C)alkynyloxy,including (3-6C)alkynyloxy, such as prop-2-ynyloxy; and (1-4C)alkanoyl,such as formyl and ethanoyl.

Examples of particular values for y are 0 and 1.

Examples of particular values for z are 0, 1, 2 and 3.

L^(a) and L^(b) preferably each independently represents CH₂.

X² preferably represents a bond, O, NH, CO, CH(OH), CONH, NHCO, NHCONHor OCH₂CONH.

Preferably the group (CH₂)_(y)X¹R⁹ represents CHO; COCH₃, OCH₃;OCH(CH₃)₂; NHCOR⁹ in which R⁹ represents methyl, ethyl, isopropyl,t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-pyrolidinyl or morpholino; CONHR⁹ in which R⁹ represents cyclopropylor cyclopentyl; NHCOCOOCH3; or 2-tetrahydrofurylmethoxy.

Preferably the group (CH₂)_(z)X³R¹⁵ represents NH₂; CH₂NH₂; (CH₂)₂NH₂;(CH₂)₃NH₂; CONH₂; CONHCH₃; CON(CH₃)₂; N(C₂H₅)₂; CH₂OH; CH(OH)CH₃;CH(OH)CH₂CH₂; CHO; COCH₃; COOH; COOCH₃; CH₂NHCOOC(CH₃)₃;(CH₂)₂NHCOOC(CH₃)₃; NHSO₂CH(CH₃)₂; a group of formula (CH₂)₂NHSO₂R¹⁵ inwhich R¹⁵ represents CH₃, CH₂CH₃, CH(CH₃)₂, (CH₂)₂CH₃, (CH₃)₃CH₃,benzyl, CH₂CF₃, 2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl,phenyl, 2-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-methoxyphenyl, 1-(2-dimethylamino)naphthyl or2-thienyl; CH(OH)CH₂NHSO₂CH₃; (CH₂)₃NHSO₂CH(CH₃)₂;COCH₂N(OCOC(CH₃)₂SO₂CH₃; COCH₂NHSO₂CH₃; (CH₂)₂NHCOR¹⁵ in which R¹⁵represents CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, phenyl, 3-fluorophenyl,4-fluorophenyl, benzyl; 2-methoxyphenyl, 4-methoxyphenyl, 2-thienyl,CH═CH, CH═CHCN, OCH₃ or O(CH₂)₃CH₃.

Examples of particular values for (L^(a))_(n)—X²—(L^(b))_(m) are a bond,O, NH, S, SO, SO₂, CO, CH₂, COCH₂, COCONH, CH(OH)CH₂, CONH, NHCO,NHCONH, CH₂O, OCH₂, OCH₂CONH, CH₂NH, NHCH₂ and CH₂CH₂.

R¹⁴ is preferably an unsubstituted or substituted phenyl, naphthyl,furyl, thienyl, isoxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrimidylbenzothienyl or benzothiazolyl group.

Examples of particular values for R¹⁴ are phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chloro-phenyl, 3-chlorophenyl,4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,4-iodophenyl, 2,3-difluoro-phenyl, 2,4-difluorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 4-cyanophenyl, 3-nitrophenyl,4-hydroxyiminophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl,3-propylphenyl, 4-t-butylphenyl, 2-prop-2-enylphenyl,4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-bromomethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-(2-cyanoethenyl)phenyl, 4-phenyl,2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 2-acetylphenyl,3-acetylphenyl, 4-acetylphenyl, 2-propanoylphenyl,2-(2-methyl-propanoyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-butoxyphenyl, 2-hydroxymethylphenyl,4-hydroxymethylphenyl, 2-(1-hydroxyethyl)phenyl,3-(1-hydroxyethyl)phenyl, 4-(1-hydroxyethyl)phenyl,2-(1-hydroxypropyl)phenyl, 4-(1-hydroxypropyl)phenyl,2-(1-hydroxy-2,2-dimethyl-propyl)phenyl, 4-trifluoromethoxyphenyl,2-aminophenyl, 4-aminophenyl, 4-N,N-diethylaminophenyl,4-aminomethylphenyl, 4-(2-aminoethyl)phenyl, 4-(3-aminopropyl)phenyl,4-carboxyphenyl, 4-carbamoylphenyl, 4-N-methylcarbamoylphenyl,4-N,N-dimethylcarbamoylphenyl, 2-isopropylaminomethylphenyl,4-t-butoxycarbonylaminomethylphenyl,4-(2-isopropoxy-carboxamido)ethylphenyl,4-(2-t-butoxycarboxamido)ethyl-phenyl, 4-isopropylsulfonylaminophenyl,4-(2-methane-sulfonylamino)ethylphenyl,4-(2-ethylsulfonylamino)ethylphenyl,4-(3-isopropylsulfonylamino)propylphenyl,4-(1-(2-(2-propane)sulfonylamino)propyl)phenyl,4-(2-propylsulfonylamino)ethylphenyl,4-(2-isopropylsulfonylamino)ethylphenyl,4-(2-butylsulfonylamino)ethylphenyl,4-(1-isopropyl-sulfonylaminomethyl)ethylphenyl,4-(1-hydroxy-2-methane-sulfonylamino)ethylphenyl,4-(2-(2,2,2-trifluoroethyl)sulfonylaminoethyl)phenyl,4-(2-cyclohexylsulfonylamino)-ethylphenyl,4-(2-(2,2,2-trifluoroethyl)sulfonylamino)-ethylphenyl,4-(2-N,N-dimethylaminosulfonylamino)-ethylphenyl,4-(2-phenylsulfonylaminoethyl)phenyl,4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(2-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-methoxyphenyl)sulfonylaminoethyl)phenyl,4-(2-(1-(5-dimethylamino)napthalenesulfonylamino)ethyl)phenyl,4-(2-(2-thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl,4-(2-(4-fluorobenzamido)ethyl)phenyl,4-(2-(3-methoxybenzamido)ethyl)phenyl,4-(2-(3-fluorobenzamido)-ethyl)phenyl,4-(2-(4-methoxybenzamido)ethyl)phenyl,4-(2(2-methoxybenzamido)ethyl)phenyl,4-(1-(2-(2-methoxycarbonylethanesulfonylamino)ethyl)phenyl,4-(1-(2-(10-camphorsulfonylamino)ethyl)phenyl,4-(1-(2-(benzylsulfonyl-amino)ethyl)phenyl,4-(2-phenylacetamido)ethyl)phenyl, 4-methanesulfonylaminoethanoylphenyl,4-(N-(t-butoxy-carbonyl)methanesulfonylaminoethanoyl)phenyl,4-(2-(2-thienylcarboxamido)ethyl)phenyl, thien-2-yl,5-hydroxy-methylthien-2-yl, 5-formylthien-2-yl, thien-3-yl,5-hydroxymethylthien-3-yl, 5-formylthien-3-yl, 2-bromothien-3-yl,fur-2-yl, 5-nitrofur-2-yl, fur-3-yl, isoxazol-5-yl,3-bromoisoxazol-5-yl, isoxazol-3-yl, 5-trimethylsilylisoxazol-3-yl,5-methylisoxazol-3-yl, 5-hydroxymethylisoxazol-3-yl,5-methyl-3-phenylisoxazol-4-yl, 5-(2-hydroxyethyl)isoxazol-3-yl,5-acetylisoxazol-3-yl, 5-carboxyisoxazol-3-yl,5-N-methylcarbamoylisoxazol-3-yl, 5-methoxycarbonylisoxazol-3-yl,3-bromo[1,2,4]oxadiazol-5-yl, pyrazol-1-yl, thiazol-2-yl,4-hydroxymethylthiazol-2-yl, 4-methoxycarbonylthiazol-2-yl,4-carboxythiazol-2-yl, imidazol-1-yl, 2-sulfhydryl-imidazol-1-yl,[1,2,4]triazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl,2-ethyltetrazol-5-yl, 2-isopropyl-tetrazol-5-yl,2-(2-propenyl)tetrazol-5-yl, 2-benzyltetrazol-5-yl, pyrid-2-yl,5-ethoxycarbonylpyrid-2-yl, pyrid-3-yl, 6-chloropyrid-3-yl, pyrid-4-yl,5-trifluoro-methylpyrid-2-yl, 6-chloropyridazin-3-yl,6-methylpyridazin-3-yl, 6-methoxypyrazin-3-yl, pyrimidin-5-yl,benzothien-2-yl, benzothiazol-2-yl, and quinol-2-yl.

Examples of an unsubstituted or substituted aromatic or heteroaromaticgroup represented by R¹ are unsubstituted or substituted phenyl, furyl,thienyl (such as 3-thienyl) and pyridyl (such as 3-pyridyl).

More preferably, R¹ represents 2-naphthyl or a group of formula

in which

R²⁰ represents halogen; nitro; cyano; hydroxyimino; (1-10C)alkyl;(2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cyclo-alkyl;hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl, halo(1-10C)alkyl;(CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO, OCONR¹³,R⁹ represents hydrogen, (1-10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl,pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R¹⁰,R¹¹, R¹² and R¹³ each independently represents hydrogen or (1-10C)alkyl,or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together with the nitrogen atom to whichthey are attached form an azetidinyl, pyrrolidinyl, piperidinyl ormorpholino group; N-(1-4C)alkylpiperazinyl;N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; tetrazolyl; pyridyl; pyridazinyl;pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl;dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyldihydrothiazolyl;(1-4C)alkoxycarbonyldimethyl-dihydrothiazolyl; tetrahydrothienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; benzothiazolyl; and a group offormula R¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) in which X² represents a bond, O,NH, S, SO, SO₂, CO, CH(OH), CONH, NHCONH, NHCOO, COCONH, OCH₂CONH orCH═CH, NHCO, L^(a) and L^(b) each represent (1-4C)alkylene, one of n andm is 0 or 1 and the other is 0, and R¹⁴ represents a phenyl orhetero-aromatic group which is unsubstituted or substituted by one ortwo of halogen; nitro; cyano; (1-10C)alkyl; (2-10C)alkenyl;(2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; (CH₂)_(z)X³R¹⁵ in which zis 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH),COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, NHSO₂NR¹⁷, NHCONH, OCONR¹⁹ or NR¹⁹COO,R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl,halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,(N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; and

R²¹ represents a hydrogen atom, a halogen atom, a (1-4C)alkyl group or a(1-4C)alkoxy group.

Examples of particular values for R²⁰ are fluorine, chlorine, bromine,cyano, hydroxyimino, methyl, ethyl, propyl, 2-propyl, butyl,2-methylpropyl, 1,1-dimethylethyl, cyclopentyl, cyclohexyl,3-hydroxycyclopentyl, 3-oxocyclopentyl, methoxy, ethoxy, propoxy,2-propoxy, acetyl, acetylamino, ethylcarboxamido, propylcarboxamido,1-butanoylamido, t-butylcarboxamido, acryloylamido,2-pyrrolidinylcarboxamido, 2-tetrahydrofurylmethoxy,morpholinocarboxamido, methyloxalylamido, cyclo-propylcarboxamido,cyclobutylcarboxamido, cyclopentylcarboxamido, cyclohexylcarboxamido,cyclopropylcarbamoyl, cyclopentylcarbamoyl, pyrrolidin-1-yl, morpholino,piperidin-1-yl, N-methylpiperazinyl, N-benzylpiperazinyl, 2-thienyl,3-thienyl, 2-furyl, 3-furyl, isoxazol-3-yl, thiazol-2-yl, tetrazol-5-yl,pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-5-yl,4,5-dihydrothiazol-2-yl, 4,5-dihydro-4-methoxycarbonylthiazol-2-yl,4,5-dihydro-4-methoxy-carbonyl-5,5-dimethylthiazol-2-yl,benzothien-2-yl, benzothiazol-2-yl, phenyl, 2-fluorophenyl,3-fluorophenyl, 2,3-difluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 3-nitrophenyl, 4-cyanophenyl, 2-methylphenyl,4-methylphenyl, 4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl,3-trifluoromethylphenyl, 4-trifluoro-methylphenyl,4-(2-cyanoethenyl)phenyl, 2-formylphenyl, 3-formylphenyl,4-formylphenyl, 3-acetylphenyl, 4-acetylphenyl, 4-carboxyphenyl,2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxymethylphenyl,4-hydroxymethylphenyl, 3-(1-hydroxyethyl)phenyl,4-(1-hydroxyethyl)phenyl, 4-(1-hydroxypropyl)phenyl, 2-aminophenyl,4-aminophenyl, 4-N,N-diethylaminophenyl, 4-aminomethylphenyl,4-(2-aminoethyl)-phenyl, 4-(3-aminopropyl)phenyl,4-(2-acetylaminoethyl)-phenyl, 4-t-butoxycarboxylaminoethyl)phenyl,4-(2-t-butoxycarboxylaminoethyl)phenyl, benzylsulfonylamino,4-isopropylsulfonylaminophenyl, 4-(2-methanesulfonylaminoethyl)phenyl,4-(2-ethylsulfonylaminoethyl)phenyl,4-(2-propylsulfonylaminoethyl)phenyl,4-(2-butylsulfonyl-aminoethyl)phenyl,4-(2-isopropylsulfonylaminoethyl)phenyl,4-(1-hydroxy-2-methanesulfonylaminoethyl)phenyl,4-(2-dimethylaminosulfonylaminoethyl)phenyl,4-(1-(2-(2-propyl)sulfonylaminopropyl)phenyl,4-(2-(2,2,2-trifluoroethyl)sulfonylaminoethyl)phenyl,4-(2-cyclohexylsulfonyl-aminoethyl)phenyl,4-(2-phenylsulfonylaminoethyl)phenyl,4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(2-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-methoxyphenyl)sulfonylaminoethyl)phenyl,4-(2-(1-(5-dimethylamino)napthalenesulfonylamino)ethyl)phenyl,4-(2-(2-thienyl)sulfonylamino)ethyl)phenyl,4-(2-benzamidethyl)-phenyl,4-(2-(4- fluorobenzamido)ethyl)phenyl,4-(2-(3-methoxybenzamido)phenyl, 4-(2-(3-fluorobenzamido)ethyl)phenyl,4-(2-(4-methoxybenzamido)ethyl)phenyl,4-(2-(2-methoxybenzamido)ethyl)phenyl,4-(2-(2-thienyl-carboxamido)ethyl)phenyl, 4-carbamoylphenyl,4-methyl-carbamoyl phenyl, 4-dimethylcarbamoylphenyl,4-(2-(2-methylpropaneamido)ethyl)phenyl,4-(2-(3-methyl-butaneamido)ethyl)phenyl, benzoylmethyl, benzamido,2-fluorobenzamido, 3-flurobenzamido, 4-fluorobenzamido,2,4-difluorobenzamido, 3-chlorobenzamido, 4-chlorobenzamido,4-bromobenzamido, 4-iodobenzamido, 4-cyanobenzamido, 3-methylbenzamido,4-methylbenzamido, 4-ethylbenzamido, 4-propylbenzamido,4-t-butylbenzamido, 4-vinylbenzamido, 2-trifluoromethylbenzamido,3-trifluoromethylbenzamido, 4-trifluoromethylbenzamido,2-fluoro-4-trifluoromethylbenzamido, 2-methoxybenzamido,3-methoxybenzamido, 4-methoxybenzamido, 4-butoxybenzamido,4-phenylphenyl-carboxamido, 4-benzylcarboxamido,4-phenoxymethyl-carboxamido, 2-fluorobenzylamino, benzyloxy,2-fluorobenzyloxy, 2-hydroxy-2-phenylethyl, 2-fluorophenylcarbamoyl,4-(1-(2-(2-methoxycarbonylethanesulfonylamino)ethyl)phenyl,4-(1-(2-(10-camphorsulfonylamino)ethyl)phenyl,4-(1-(2-(benzylsulfonylamino)ethyl)phenyl,4-(2-phenylacetamido)-ethyl)phenyl,4-(methanesulfonylaminoethanoyl)phenyl,4-(N-t-butoxycarbonyl)methanesulfonylaminoethanoyl)phenyl,2-thienylcarboxamido, 2-furylcarboxamido,3-(5-methyl-isoxazolyl)carboxamido, 5-isoxazolylcarboxamido,2-benzothienylcarboxamido, 4-(5-methyl-3-phenylisoxazolyl)-carboxamido,4-pyridylcarboxamido, 2-(5-nitrofuryl)carboxamido, 2-pyridylcarboxamido,6-chloro-2-pyridyl-carboxamido, 2-thienylsulfonamido,2-thienylmethylamino, 3-thienylmethylamino, 2-furylmethylamino,3-furylmethylamino, 3-acetylureido and 2-(2-thienyl)ethylureido.

Examples of particular values for R²¹ are hydrogen and chlorine. R²¹ ispreferably ortho to R²⁰.

Examples of particular values for R¹ are 2-naphthyl, 4-bromophenyl,4-cyanophenyl, 4-benzamidophenyl, 4-methylphenyl, 4-isopropyl-phenyl,4-isobutylphenyl, 4-t-butylphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl,4-cyclopentylphenyl, 4-cyclohexylphenyl,4-(2-hydroxymethylphenyl)phenyl, 4-(4-hydroxymethylphenyl)-phenyl,4-(2-furyl)phenyl, 4-(3-furyl)phenyl, 4-(2-thienyl)phenyl,4-(3-thienyl)phenyl, 4-(pyrrolidin-1-yl)phenyl,4-(piperidin-1-yl)phenyl, 3-chloro-4-piperidin-1-ylphenyl,4-benzyloxyphenyl, 4-(2-fluorophenyl)phenyl, 4-(3-fluoro-phenyl)phenyl,4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)-phenyl,4-(4-formylphenyl)phenyl, 4-(4-methylphenyl)phenyl and4-(2-methoxyphenyl)phenyl.

The compounds of formula I can be prepared as described in Scheme Ibelow. The reagents and starting materials are readily available to oneof ordinary skill in the art. All the substituents, unless otherwisespecified are previously defined.

In Scheme I, the compound of formula II is reacted with the compound offormula III under standard conditions well known in the art, to providethe compound of formula I. More specifically, the compound of formula IIis dissolved in a suitable organic solvent. Examples of suitable organicsolvents include methylene chloride, tetrahydrofuran, ethyl acetate,acetonitrile, and the like. The solution is treated with a slight excessof a suitable base, and then cooled to about −78° C. to about 0° C.Examples of suitable bases include triethylamine, DBU, pyridine, and thelike. To the stirring solution is added one equivalent of a compound offormula III. The term “Lg” as used herein refers to a suitable leavinggroup. Examples of suitable leaving groups include, Cl, Br, F, I, andthe like. Cl is the preferred leaving group. The reaction mixture isstirred at about 0° C. to about 50° C. for about 0.5 hours to about 16hours. The compound of formula I is then isolated and purified bytechniques well known in the art, such as extraction techniques andchromatography.

For example, the reaction is treated with a suitable acid, such asdilute hydrochloric acid, to neutralize or make the solution slightlyacidic and then extracted with a suitable organic solvent, such asmethylene chloride. The organic extracts are combined, dried overanhydrous magnesium sulfate, filtered and concentrated under vacuum toprovide the crude material of formula I. The crude material can bepurified by flash chromatography on silica gel with a suitable eluent toprovide the purified compound of formula I. Examples of suitable eluentsare ethyl acetate, hexanes, and the like.

Compounds of formula III can be prepared following the proceduredescribed in Scheme II. Unless otherwise indicated, the substituents arepreviously defined. The reagents and starting materials are readilyavailable to one of ordinary skill in the art.

In Scheme II, step A, the compound of structure (1) is treated with anequivalent of thiourea (2) in a suitable organic solvent, such as 95%ethanol. Lg′ represents a suitable leaving group. Examples of suitableleaving groups are Br, Cl, F, I, and the like. Br is the preferredleaving group. The reaction mixture is heated at about 80° C. for about60 hours. After cooling, the reaction mixture is concentrated undervacuum and the residue is suspended in a suitable organic solvent, suchas diethyl ether. The solid is then collected by filtration and thendissolved in water with heat. To this solution is added a slight excessof potassium acetate to provide the compound (3) which can be collectedby filtration and dried under vacuum.

In Scheme II, step B, compound (3) is oxidized under standard conditionsto provide the compound of formula III. For example, compound (3) isdissolved in water and cooled to about 0° C. To this solution is added acatalytic amount of hydrochloric acid and chlorine gas is bubble throughthe solution for about 3 to 5 hours. The reaction mixture is thenextracted with a suitable organic solvent, such as methylene chloride.The organic extracts are combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to provide the compound offormula III.

The compounds of formula Ia and formula Ib can be prepared accordingScheme III. Unless otherwise indicated, the substituents are previouslydefined. The reagents and starting materials are readily available toone of ordinary skill in the art.

In Scheme III, step A, the compound of structure (4) is treated with anamine of structure (5) in a manner analogous to the procedure ofdescribed above in Scheme I to provide the sulfonamide of structure (6).

In Scheme III, step B, the compound of structure (6) is converted to ananion under conditions well known to one of ordinary skill in the art,and then reacted with the compound of structure (7) to provide thealcohol of structure (8). For example, compound (6) is dissolved in asuitable organic solvent, such as tetrahydrofuran and cooled to about−78° C. It is then treated with about two equivalents of a suitablebase, such as n-butyllithium. The reaction mixture is allowed to warm toabout 0° C., over one to two hours and then cooled back to about −78° C.To this solution is added an excess of a compound (7) and the reactionmixture is allowed to warm to room temperature. It is then quenched withwater and the alcohol (8) is isolated and purified by techniques wellknown in the art, such as extraction techniques and chromatography. Forexample, the quenched reaction mixture is extracted with a suitableorganic solvent, such as diethyl ether, the organic extracts arecombined, dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum. The crude product can then be purified forexample by flash chromatography on silica gel with a suitable eluent,such as ethyl acetate/hexanes to provide the purified alcohol (8).

In Scheme III, step C, the alcohol (8) is reduced under standardconditions well known to one of ordinary skill in the art to provide thecompound of formula Ia. For example, the alcohol (8) is dissolved in asuitable organic solvent, such as methylene chloride and treated with anexcess of trifluoroacetic acid. To this mixture is then added an excessof triethylsilane and the reaction is stirred for about 2 to 4 hours ata temperature of about 23° C. to reflux. The product is then isolatedand purified using standard techniques. For example, the reactionmixture is concentrated under vacuum and the crude residue is purifiedby flash chromatography on silica gel with a suitable eluent, such asethyl acetate/hexanes to provide the purified compound of formula Ia.

In Scheme III, step C′, the alcohol (8) can be reduced under conditionsanalogous to those described in Step C to provide the compound offormula Ib using only one equivalent of trifluoroacetic acid instead ofemploying excess trifluoroacetic acid.

In Scheme III, step D, the compound of formula Ia can be alkylated underconditions well known in the art to provide the compound of formula Ib.For example, see J. March, “Advanced Organic Chemistry Reactions,Mechanisms, and Structure,” 2nd Edition, McGraw-Hill, Inc. (1977) pages377-378.

The compounds of formula I in which R¹ represents a 4-bromophenyl groupmay conveniently be converted into other compounds of formula I in whichR represents another 4-substituted phenyl group by reaction with anappropriate boronic acid derivative, for example, a benzeneboronic acidderivative. The reaction is conveniently performed in the presence of atetrakis (triarylphosphine)palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base such as potassium carbonate.Convenient solvents for the reaction include aromatic hydrocarbons, suchas toluene. The temperature at which the reaction is conducted isconveniently in the range of from 0 to 150° C., preferably 75 to 120° C.Bis aromatic intermediates useful in the preparation of compounds offormula I may be prepared by reacting a bromoaromatic orbromoheteroarbmatic compound with an aromatic or heteroaromatic boronicacid in an analogous manner.

More specifically, for example, to a degassed solution of a compound offormula I wherein R¹ represents a 4-bromophenyl group, approximately 1.5equivalents of a benzeneboronic acid derivative, such as3-fluorobenzeneboronic acid, and approximately 1.5 equivalents ofpotassium carbonate in a suitable organic solvent, such as toluene, isadded a catalytic amount of bis(triphenyl-phosphine)palladium(II)dichloride. The mixture is heated to about 100° C. for about 16 hours,cooled to ambient temperature and diluted with ethyl acetate. Themixture is washed with water and the organic portion is separated. Theaqueous portion is extracted with ethyl acetate and the combinedorganics are dried anhydrous magnesium sulfate, filtered andconcentrated under vacuum. Chromatography on silica gel with a suitableeluent, such as ethyl acetate/toluene provides the desired bis aromaticcompound of formula I.

The boronic acid derivative used as a starting material may be preparedby reacting a trialkyl borate, such as triisopropyl borate with anappropriate organolithium compound at reduced temperature. For example,2-fluorobenzeneboronic acid may be prepared by reacting2-fluorobromobenzene with butyllithium in tetrahydrofuran at about −78°C. to afford 2-fluorophenyl lithium, and then reacting thisorganolithium compound with triisopropyl borate.

Alternatively, the compounds of formula I in which R¹ represents a4-bromophenyl group may be converted to a 4-(trimethylstannyl)phenyl or4-(tri-n-butylstannyl)phenyl group by treatment of the correspondingbromide with a palladium(0) catalyst, such astetrakis(triphenylphosphine)-palladium(0) and hexaalkyldistannane, wherethe alkyl group is methyl or n-butyl, in an aprotic solvent such astoluene in the presence of a tertiary amine base such as triethylamine,at temperatures ranging from 80 to 140° C., preferably from 90 to 110°C.

The compounds of formula I in which R¹ represents a4-(tri-n-butylstannyl)phenyl group may then be reacted with an aryl- orheteroarylbromide, such as 2-bromothiophene-5-carboxaldehyde, in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), or a palladium(II) catalyst,such as bis(triphenylphosphine)-palladium(II) dichloride, in an aproticsolvent, such as dioxane, at temperatures ranging from 80 to 140° C.,preferably from 90 to 110° C., to afford the corresponding4-(aryl)phenyl or 4-(heteroaryl)phenyl substituted compound.

The compounds of formula I in which R¹ represents a 4-bromophenyl groupmay be converted into other compounds of formula I in which R¹represents a 4-substituted alkyl- or cycloalkylphenyl group, such as4-cyclopentylphenyl by treatment of the corresponding bromide with anappropriate alkyl- or cycloalkyl Grignard reagent, such ascyclopentyl-magnesium bromide, in the presence of a palladium(II)catalyst, such as[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)(PdCl₂(dppf)),in an aprotic solvent, such as diethyl ether at temperatures rangingfrom −78° C. to 25° C.

The compounds of formula I in which R¹ represents a 4-bromophenyl groupmay be converted into a 4-substitutedcarboxyaldehydephenyl(formylphenyl) group by reaction of thecorresponding bromide with the carbon monoxide gas which is bubbled intothe reaction under atmospheric pressure in the presence of apalladium(II) catalyst, such as bis(triphenyl-phosphine)palladium(II)dichloride and sodium formate in an aprotic solvent, such asdimethylformamide at temperatures ranging from 70 to 110° C., preferablyat 90° C.

The compounds of formula I in which R¹ represents a 4-hydroxyphenylgroup may be converted into other compounds of formula I in which R¹represents an alkoxy group by treatment of the correspondinghydroxyphenyl group with an appropriate alkylhalide such asbenzylbromide in the presence of sodium hydride in an aprotic solventsuch as dimethylformamide at temperatures ranging from 25 to 100° C.,preferably from 50 to 90° C.

The ability of compounds of formula I to potentiate glutamatereceptor-mediated response may be determined using fluorescent calciumindicator dyes (Molecular Probes, Eugene, Oreg., Fluo-3) and bymeasuring glutamate-evoked efflux of calcium into GluR4 transfectedHEK293 cells, as described in more detail below.

In one test, 96 well plates containing confluent monolayers of HEK cellsstably expressing human GluR4B (obtained as described in European PatentApplication Publication Number EP-A1-583917) are prepared. The tissueculture medium in the wells is then discarded, and the wells are eachwashed once with 200 μl of buffer (glucose, 10 mM, sodium chloride, 138mM, magnesium chloride, 1 mM, potassium chloride, 5 mM, calciumchloride, 5 mM, N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid],10 mM, to pH 7.1 to 7.3). The plates are then incubated for 60 minutesin the dark with 20 μM Fluo3-AM dye (obtained from Molecular ProbesInc., Eugene, Oreg.) in buffer in each well. After the incubation, eachwell is washed once with 100 μl buffer, 200 μl of buffer is added andthe plates are incubated for 30 minutes.

Solutions for use in the test are also prepared as follows. 30 μM, 190μM, 3 μM and 1 μM dilutions of test compound are prepared using bufferfrom a 10 mM solution of test compound in DMSO. 100 μM cyclothiazidesolution is prepared by adding 3 μl of 100 mM cyclothiazide to 3 ml ofbuffer. Control buffer solution is prepared by adding 1.5 μl DMSO to498.5 μl of buffer.

Each test is then performed as follows. 200 μl of control buffer in eachwell is discarded and replaced with 45 μl of control buffer solution. Abaseline fluorescent measurement is taken using a FLUOROSKAN IIfluorimeter (Obtained from Labsystems, Needham Heights, Mass., USA, aDivision of Life Sciences International Plc). The buffer is then removedand replaced with 45 μl of buffer and 45 μl of test compound in bufferin appropriate wells. A second fluorescent reading is taken after 5minutes incubation. 15 μl of 400 μM glutamate solution is then added toeach well (final glutamate concentration 100 μM), and a third reading istaken. The activities of test compounds and cyclothiazide solutions aredetermined by subtracting the second from the third reading(fluorescence due to addition of glutamate in the presence or absence oftest compound or cyclothiazide) and are expressed relative to enhancefluorescence produced by 100 μM cyclothiazide.

In another test, HEK293 cells stably expressing human GluR4 (obtained asdescribed in European Patent Application Publication No. EP-A1-0583917)are used in the electro-physiological characterization of AMPA receptorpotentiators. The extracellular recording solution contains (in mM): 140NaCl, 5 KCl, 10 HEPES, 1 MgCl₂, 2 CaCl₂, 10 glucose, pH=7.4 with NaOH,295 mOsm kg−1. The intracellular recording solution contains (in mM):140 CsCl, 1 MgCl₂, 10 HEPES,(N-[2-hydroxyethyl]piperazine-N1-[2-ethanesulfonic acid]) 10 EGTA(ethylene-bis(oxyethylene-nitrilo)tetraacetic acid), pH 7.2 with CsOH,295 mOsm kg−1. With these solutions, recording pipettes have aresistance of 2-3 MΩ. Using the whole-cell voltage clamp technique(Hamill et al.(1981) Pflügers Arch., 391: 85-100), cells arevoltage-clamped at −60 mV and control current responses to 1 mMglutamate are evoked. Responses to 1 mM glutamate are then determined inthe presence of test compound. Compounds are deemed active in this testif, at a test concentration of 10 μM, they produce a greater than 30%increase in the value of the current evoked by 1 mM glutamate.

In order to determine the potency of test compounds, the concentrationof the test compound, both in the bathing solution and co-applied withglutamate, is increased in half log units until the maximum effect wasseen. Data collected in this manner are fit to the Hill equation,yielding an EC₅₀ value, indicative of the potency of the test compound.Reversibility of test compound activity is determined by assessingcontrol glutamate 1 mM responses. Once the control responses to theglutamate challenge are re-established, the potentiation of theseresponses by 100 μM cyclothiazide is determined by its inclusion in boththe bathing solution and the glutamate-containing solution. In thismanner, the efficacy of the test compound relative to that ofcyclothiazide can be determined.

According to another aspect, the present invention provides apharmaceutical composition, which comprises a compound of formula I ora, pharmaceutically acceptable salt thereof as defined hereinabove and apharmaceutically acceptable diluent or carrier.

The pharmaceutical compositions are prepared by known procedures usingwell-known and readily available ingredients. In making the compositionsof the present invention, the active ingredient will usually be mixedwith a carrier, or diluted by a carrier, or enclosed within a carrier,and may be in the form of a capsule, sachet, paper, or other container.When the carrier serves as a diluent, it may be a solid, semi-solid, orliquid material which acts as a vehicle, excipient, or medium for theactive ingredient. The compositions can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols, ointments containing, forexample, up to 10% by weight of active compound, soft and hard gelatincapsules, suppositories, sterile injectable solution's, and sterilepackaged powders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia,calcium phosphate, alginates, tragcanth, gelatin, calcium silicate,micro-crystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc,magnesium stearate, and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents, or flavoring agents.Compositions of the invention may be formulated so as to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 mg to about 500 mg, more preferably about5 mg to about 300 mg (for example 25 mg) of the active ingredient. Theterm “unit dosage form” refers to a physically discrete unit suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical carrier, diluent, or excipient. The following formulationexamples are illustrative only and are not intended to limit the scopeof the invention in any way.

FORMULATION 1

Hard gelatin capsules are prepared using the following ingredients:

Quantify (mg/capsule) Active Ingredient 250 Starch, dried 200 MagnesiumStearate 10 Total 460

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

FORMULATION 2

Tablets each containing 60 mg of active ingredient are made as follows:

Quantity (mg/tablet) Active ingredient 60 Starch 45 MicrocrystallineCellulose 35 Polyvinylpyrrolidone 4 Sodium Carboxymethyl Starch 4.5Magnesium Stearate 0.5 Talc 1 Total 150

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

As used herein the term “patient” refers to a mammal, such a mouse,guinea pig, rat, dog or human. It is understood that the preferredpatient is a human.

As used herein the term “effective amount” refers to the amount or doseof the compound which provides the desired effect in the patient underdiagnosis or treatment.

The particular dose of compound administered according to this inventionwill of course be determined by the particular circumstances surroundingthe case, including the compound administered, the route ofadministration, the particular condition being treated, and similarconsiderations. The compounds can be administered by a variety of routesincluding oral, rectal, transdermal, subcutaneous, intravenous,intramuscular, or intranasal routes. Alternatively, the compound may beadministered by continuous infusion. A typical daily dose will containfrom about 0.01 mg/kg to about 100 mg/kg of the active compound of thisinvention. Preferably, daily doses will be about 0.05 mg/kg to about 50mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.

The following examples represent typical syntheses of compounds withinformula I as described generally above. These examples are illustrativeonly and are not intended to limit the invention in any way. Thereagents and starting materials are readily available to one of ordinaryskill in the art. As used herein, the following terms have the meaningsindicated: “eq” refers to equivalents; “g” refers to grams; “mg” refersto milligrams; “L” refers to liters; “mL” refers to milliliters; “μL”refers to microliters; “mol” refers to moles; “mmol” refers tomillimoles; “psi” refers to pounds per square inch; “min” refers tominutes; “h” refers to hours; “° C.” refers to degrees Celsius; “TLC”refers to thin layer chromatography; “HPLC” refers to high performanceliquid chromatography; “R_(f)” refers to retention factor; “R_(t)”refers to retention time; “δ” refers to part per million down-field fromtetramethylsilane; “THF” refers to tetrahydrofuran; “DMF” refers toN,N-dimethylformamide; “DMSO” refers to methyl sulfoxide “LDA” refers tolithium diisopropylamide; “aq” refers to aqueous; “TFA” refers totrifluoroacetic acid: “iPrOAc” refers to isopropyl acetate; “Me” refersto a methyl group: “Et” refers to an ethyl group: “iPr” refers to anisopropyl group; “Bu” refers to a butyl group; “EtOAc” refers to ethylacetate; and “RT” refers to room temperature.

EXAMPLE 1 Preparation of N-(2-Propyl)-1-(2-phenylpropanesulfonamide)

Scheme II, step A: S-2-phenylpropylthiuronium acetate: A solution of10.0 g (50.2 mmol) of 1-bromo-2-phenylpropane and 3.8 g (50.2 mmol) ofthiourea in 30 mL of 95% ethanol was heated to 80° C. for 60 hours. Thereaction mixture was cooled to room temperature and concentrated invacuo. The residue was suspended in 100 mL of diethyl ether, filteredand air dried. The solid was dissolved in 120 mL of water at 80° C. and20 mL of saturated aqueous potassium acetate was added. After cooling toroom temperature, the resulting crystals were filtered and driedconcentrated in vacuo to afford 10.2 g (80%) of the title compound.

Scheme II, step B: 2-phenylpropanesulfonyl chloride: Through a 0° C.suspension of 18.2 g (40.0 mmol) of material from step A in 100 mL ofwater and 1.1 mL of concentrated hydrochloric acid was bubbled chlorinegas slowly for three hours. The mixture was extracted three times with50 mL each of dichloromethane. The combined organics were dried(Na₂SO₄), filtered and concentrated in vacuo to afford 6.6 g (75%) ofthe title compound as a yellow oil.

Scheme I: To a 0° C. solution of 0.2 g (2.3 mmol) of 2-propylamine and0.2 g (2.3 mmol) of triethylamine in 10 mL of dichloromethane was added0.5 g (2.3 mmol) of material from step B and the mixture was stirred for20 minutes. The mixture was washed once with 10 mL of 10% aqueous sodiumbisulfate. The organic portion was separated and the aqueous portion wasextracted once with 5 mL of dichloromethane. The combined organicportions were dried (Na₂SO₄), filtered and concentrated in vacuo.Chromatography (50 g of silica gel, 25% ethyl acetate/hexanes) of theresidue afforded 0.3 g (47%) of the title compound.

Electrospray Mass Spectrum: M=241.

EXAMPLE 2 Preparation ofN-t-Butyl-2-(4-bromophenyl)-2-hydroxypropanesulfonamide

Scheme III, step A: N-t-butyl methanesulfonamide: To a 0° C. solution of10 g (136.7 mmol) of t-butylamine and 15.2 g (150.4 mmol) oftriethylamine in 350 mL of dichloromethane was added 15.7 g (136.7 mmol)of methanesulfonyl chloride in 20 mL of dichloromethane over 15 minutes.Continue stirring at 0° C. for 30 minutes then warm to room temperatureover one hour. The mixture was washed once with 250 mL of 10% aqueoussodium bisulfate. The organic portion was separated and the aqueousportion was extracted two times with 100 mL each of dichloromethane. Thecombined organics were dried (Na₂SO₄), filtered and concentrated invacuo. The residue was recrystallized from petroleum ether and dried invacuo to afford 12.2g (59%) N-t-butyl methanesulfonamide.

Scheme III, step B: To a −78° C. solution of 0.7 g (4.7 mmol) ofN-t-butyl methanesulfonamide (from step A above) in 15 mL oftetrahydrofuran was added 6.1 mL (9.77 mmol) of 1.6 M n-butyllithium intetrahydrofuran slowly. The mixture was allowed to warm to 0° C. overone hour. The mixture was cool to −78° C. and a solution of 1.0 g (5.0mmol) of 4-bromoacetophenone in 8 mL of tetrahydrofuran was added over 5minutes. The mixture was warmed to room temperature over one hour andquenched with 10 mL of water.

The mixture was extracted three times with 10 mL each of diethyl etherand the combined organics were dried (MgSO₄), filtered and concentratedin vacuo. Chromatography (50 g of silica gel, 20% ethyl acetate/hexanes)of the residue afforded 0.9 g (49%) of the title compound.

Field Desorption Mass Spectrum: M+1=351. Analysis calculated forC₁₃H₂₀NO₃BrS: %C, 44.58; %H, 5.76; %N, 4.00. Found: %C, 44.60; %H, 5.51;%N, 4.02.

EXAMPLE 3 Preparation of 2-(4-Bromophenyl)propanesulfonamide

Scheme III, step C: To a solution of 0.8 g (2.23 mmol) ofN-t-butyl-2-(4-bromophenyl)-2-hydroxypropanesulfonamide (prepared inexample 2) in 6 mL of dichloromethane was added 0.8 g (6.7 mmol) oftrifluoroacetic acid. To this mixture was added 0.3 g (4.5 mmol) oftriethylsilane and the mixture was stirred at room temperature for twohours. To the mixture was added 0.3 mL (4.5 mmol) more of triethylsilaneand the mixture was heated to reflux for 16 hours. The mixture wascooled to room temperature and concentrated in vacuo.

Chromatography (50 g of silica gel, 30% ethyl acetate/hexanes) of theresidue afforded 0.27 g (44%) of the title compound.

Field Desorption Mass Spectrum: M-1=277. Analysis calculated forC₉H₁₂NO₂BrS: %C, 38.86; %H, 4.35; %N, 5.04. Found: %C, 39.24; %H, 4.30;%N, 5.09.

EXAMPLE 4 Preparation ofN-Methyl-2-(4-(2-fluorophenyl)phenyl)propanesulfonamide

A. 4-(2-fluorophenyl)acetophenone: To a degassed solution of 10.0 g(50.2 mmol) of 4-bromoacetophenone, 10.5 g (75.3 mmol) of2-fluorobenzeneboronic acid and 10.4 g (75.3 mmol) of potassiumcarbonate was added 4.4 g (3.8 mmol) oftetrakis(triphenylphosphine)palladium(0). The mixture was heated to 100°C. for 16 hours, cooled to room temperature and diluted with 50 mL ofwater. The mixture was extracted three times with 100 mL each of diethylether and the combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (600 g of silica gel, 10% ethylacetate/hexanes) of the residue afforded 6.2 g (58%) of4-(2-fluorophenyl)acetophenone.

B. 2-(4-(2-fluorophenyl)phenyl)methoxypropene: To a 0° C. suspension of14.7 g (43.0 mmol) of methoxymethyltriphenylphosphonium chloride in 60mL of tetrahydrofuran was added 43.0 mL (43.0 mmol) of 1.0 M sodiumbis(trimethylsilyl)amide in tetrahydrofuran and the mixture stirred for20 minutes. To the mixture was added 6.1 g (mmol) of4-(2-fluorophenyl)acetophenone in 20 mL of tetrahydrofuran and themixture was stirred at 0° C. for two hours. To the mixture was added 75mL of water and the mixture was extracted three times with 50 mL each ofdiethyl ether. The organics were dried (MgSO₄), filtered andconcentrated in vacuo. The residue was dissolved in 30 mL ofdichloromethane and filtered through three inches of silica gel in a 350mL sintered glass funnel eluting with 25% ethyl acetate/hexanes. Thefiltrate was concentrated in vacuo to afford 7.0 g (100%) of2-(4-(2-fluorophenyl)phenyl)methoxypropene.

C. 2-(4-(2-fluorophenyl)phenyl)propionaldehyde: To a solution of 7.0 g(28.8 mmol) of 2-(4-(2-fluorophenyl)phenyl)methoxypropene in 130 mL ofacetonitrile was added 35 mL of 1 N hydrochloric acid. The mixture wasstirred at room temperature for 16 hours. To this mixture was added 10mL of 5 N hydrochloric acid and stirring was continued for 16 hours. Tothe mixture was added 100 mL of brine and the mixture was extracted fourtimes with 100 mL each of diethyl ether. The organics were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (300 g ofsilica gel, 5% ethyl acetate/hexanes) of the residue afforded 4.4 g(67%) of 2-(4-(2-fluorophenyl)phenyl)propionaldehyde.

D. 2-(4-(2-fluorophenyl)phenyl)propanol: To a 0° C. solution of 4.4 g(19.3 mmol) of 2-(4-(2-fluorophenyl)phenyl)propionaldehyde in 70 mL ofethyl alcohol was added 0.7 g (19.3 mmol) of sodium borohydride and themixture was allowed to warm to room temperature over 16 hours. Thereaction mixture was concentrated in vacuo and partitioned between 50 mLof ethyl acetate and 50 mL of water. The organic portion was separatedand the aqueous portion was extracted three times with 30 mL each ofethyl acetate. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo to afford 4.2 g (94%) of2-(4-(2-fluorophenyl)phenyl)propanol.

E. 1-bromo-2-(4-(2-fluorophenyl)phenyl)propane: To a 0° C. solution of7.7 g (29.3 mmol) of triphenylphosphine in 45 mL of dichloromethane wasadded bromine until a pale yellow color persisted. Add to this mixturewas just enough triphenylphosphine to dissipate the yellow color. Tothis mixture was added 4.2 g (18.2 mmol) of2-(4-(2-fluorophenyl)phenyl)propanol and 2.3 g (29.3 mmol) of pyridinein 15 mL of dichloromethane. This mixture was stirred at 0° C. for onehour and allowed to warm to room temperature over one hour. The reactionmixture was washed once with 40 mL of 10% aqueous sodium bisulfate. Theorganic portion was separated and the aqueous portion was extracted twotimes with 25 mL each of dichloromethane. The combined organics weredried (Na₂SO₄), filtered and concentrated in vacuo. Chromatography (150g of silica gel, hexanes) of the residue afforded 4.8 g (90%) of1-bromo-2-(4-(2-fluorophenyl)phenyl)propane.

F. S-2-(4-(2-fluorophenyl)phenyl)propylthiuronium acetate was preparedin a manner analogous to the procedure described in example 1, Part A,starting from the product of part E above.

G. 2-(4-(2-fluorophenyl)phenyl)propanesulfonyl chloride was prepared ina manner analogous to the procedure described in example 1, Part B;starting from the product of part F above.

H. To 10 mL of 40% aqueous methylamine was added 0.3 g (1.0 mmol) of2-(4-(2-fluorophenyl)phenyl)propanesulfonyl chloride above in 3 mL oftetrahydrofuran and the mixture stirred at room temperature for 16hours. The reaction mixture was extracted three times with 5 mL each ofethyl acetate. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (25 g of silica gel, 35% ethylacetate/hexanes) of the residue afforded 0.1 g (42%) of the titlecompound.

Field Desorption Mass Spectrum: M=307.

EXAMPLE 5 Preparation ofN-Ethyl-2-(4-(2-fluorophenyl)phenyl)propanesulfonamide

The title compound was prepared in a manner analogous to the proceduredescribed in example 4, Part H, and using 1.0 mL (2.1 mmol) of 2 Methylamine in tetrahydrofuran to afford 0.1 g (31%).

Field Desorption Mass Spectrum: M=321.

EXAMPLE 6 Preparation ofN-(2-Propyl)-2-(4-(2-fluorophenyl)phenyl)propanesulfonamide

The title compound was prepared in a manner analogous to the proceduredescribed in example 4, Part H, and using 2-propylamine to afford 0.1 g(34%).

Field Desorption Mass Spectrum: M=335.

EXAMPLE 7 Preparation ofN,N-Dimethyl-2-(4-(2-fluorophenyl)phenyl)propanesulfonamide

The title compound was prepared in a manner analogous to the proceduredescribed in example 4, Part H and using dimethylamine to afford 0.1 g(37%).

Field Desorption Mass Spectrum: M=321.

EXAMPLE 8 Preparation ofN-(N′,N′-Dimethylpropyl)-2-(4-(2-fluorophenyl)phenyl)propane-sulfonamide

The title compound was prepared in a manner analogous to the proceduredescribed in example 4, Part H and using N,N-dimethylaminopropylamine toafford 0.1 g (23%).

Field Desorption Mass Spectrum: M=378.

EXAMPLE 9 Preparation ofN-t-Butyl-2-(4-(2-fluorophenyl)phenyl)propanesulfonamide

The title compound was prepared in a manner analogous to the proceduredescribed in example 4, Part H and using t-butylamine to afford 0.1 g(31%).

Field Desorption Mass Spectrum: M=349.

Additional compounds included within the scope of the present inventioninclude but are not limited to those listed in Table I. The compoundsillustrated in Table I can be readily prepared by one of ordinary skillin the art using standard techniques and methods well known in the artin a manner analogous to the procedures described herein from readilyavailable starting materials and from starting materials specificallydescribed hereinabove.

TABLE I Example Compound 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

We claim:
 1. A compound of the formula:

wherein R¹ represents a phenyl, which is unsubstituted or substituted byone or two substituents selected independently from halogen;(1-10C)alkyl; and a group of formula R¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) inwhich X² represents a bond, L^(a) and L^(b) each represent(1-4C)alkylene, n and m is 0, and R¹⁴ represents a phenyl which isunsubstituted or substituted by one or two of halogen, or (1-10C) alkyl,R^(2a) and R^(2b) each independently represent hydrogen, or (1-6C)alkyl,and either one of R⁵, R⁶, R⁷ and R⁸ represents hydrogen, or (1-6C)alkyl,and the remainder of R⁵, R⁶, R⁷ and R⁸ represent hydrogen; or apharmaceutically acceptable salt thereof; with the proviso that ifR^(2a) represents hydrogen, then R^(2b) represents (1-6C)alkyl.
 2. Acompound according to claim 1 wherein R^(2a) and R^(2b) eachindependently represent hydrogen, methyl, ethyl, 2-propyl, or t-butyl.3. A compound according to claim 1 wherein R^(2a) represents hydrogenand R^(2b) represents (1-6C)alkyl.
 4. A compound according to claim 1wherein R⁶ and R⁷ represent hydrogen.
 5. A compound according to claim 1wherein R⁵ and R⁸ are each independently hydrogen or (1-4C)alkyl.
 6. Acompound according to claim 5 wherein R⁸ represents methyl and R⁵represents hydrogen.
 7. A compound as claimed in claim 1, which isselected from: N-(2-propyl)-1-(2-phenylpropanesulfonamide);2-(4-bromophenyl)propanesulfonamide;N-methyl-2-(4-(2-fluorophenyl)phenyl)propanesulfonamide;N-ethyl-2-(4-(2-fluorophenyl)phenyl)propanesulfonamide;N-(2-propyl)-2-(4-(2-fluorophenyl)phenyl)propanesulfonamide;N,N-dimethyl-2-(4-(2-fluorophenyl)phenyl)propanesulfonamide;N-t-butyl-2-(4-(2-fluorophenyl)phenyl)propanesulfonamide; andpharmaceutically acceptable salts thereof.
 8. A pharmaceuticalcomposition, which comprises a compound as claimed in claim 1 and apharmaceutically acceptable diluent or carrier.
 9. A method ofpotentiating glutamate receptor function in a mammal requiring suchtreatment, which comprises administering an effective amount of acompound of formula:

wherein R¹ represents a phenyl, which is unsubstituted or substituted byone or two substituents selected independently from halogen;(1-10C)alkyl; and a group of formula R¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) inwhich X² represents a bond, L^(a) and L^(b) each represent(1-4C)alkylene, n and m is 0, and R¹⁴ represents a phenyl which isunsubstituted or substituted by one or two of halogen, or (1-10C) alkyl,R^(2a) and R^(2b) each independently represent hydrogen, or (1-6C)alkyl,and either one of R⁵, R⁶, R⁷ and R⁸ represents hydrogen, or (1-6C)alkyl,and the remainder of R⁵, R⁶, R⁷ and R⁸ represent hydrogen; or apharmaceutically acceptable salt thereof.
 10. A method of treating acognitive disorder; a neuro-degenerative disorder; age-related dementia;age-induced memory impairment; movement disorder; reversal of adrug-induced state; depression; attention deficit disorder; attentiondeficit hyperactivity disorder; psychosis; cognitive deficits associatedwith psychosis; or drug-induced psychosis in a patient, which comprisesadministering to a patient in need thereof an effective amount of acompound of formula:

wherein R¹ represents a phenyl, which is unsubstituted or substituted byone or two substituents selected independently from halogen;(1-10C)alkyl; and a group of formula R¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) inwhich X² represents a bond, L^(a) and L^(b) each represent(1-4C)alkylene, n and m is 0, and R¹⁴ represents a phenyl which isunsubstituted or substituted by one or two of halogen, or (1-10C) alkyl,R^(2a) and R^(2b) each independently represent hydrogen, or (1-6C)alkyl,and either one of R⁵, R⁶, R⁷ and R⁸ represents hydrogen, or (1-6C)alkyl,and the remainder of R⁵, R⁶, R⁷ and R⁸ represent hydrogen; or apharmaceutically acceptable salt thereof.
 11. A method for improvingmemory or learning ability in a patient, which comprises administeringto a patient in need thereof an effective amount of a compound offormula:

wherein R¹ represents a phenyl, which is unsubstituted or substituted byone or two substituents selected independently from halogen;(1-10C)alkyl; and a group of formula R¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) inwhich X² represents a bond, L^(a) and L^(b) each represent(1-4C)alkylene, n and m is 0, and R¹⁴ represents a phenyl which isunsubstituted or substituted by one or two of halogen, or (1-10C) alkyl,R^(2a) and R^(2b) each independently represent hydrogen, or (1-6C)alkyl,and either one of R⁵, R⁶, R⁷ and R⁸ represents hydrogen, or (1-6C)alkyl,and the remainder of R⁵, R⁶, R⁷ and R⁸ represent hydrogen; or apharmaceutically acceptable salt thereof.